Mechanisms of thrombin-induced tolerance to brain injury

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EXCEED THE SPACE PROVIDED. Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke and produces severe neurologic deficits in survivors. Brain injury after ICH appears to involve several phases. These include an early phase involving the clotting cascade and thrombin production and a later phase involving erythrocyte lysis and hemoglobin toxicity. Although high concentrations of thrombin cause brain edema and cell death, low concentrations are neuroprotective. Thus, we have found that prior treatment with a low dose of thrombin attenuates the brain edema induced by thrombin or hemorrhage, and significantly reduces the infarct size in a rat middle cerebral artery occlusion model. We have termed this phenomenon thrombin preconditioning (TPC). In our recent studies, we have found that TPC not only reduces brain edema induced by high dose thrombin, but also attenuates edema induced by lysed erythrocytes and FeCI2. TPC appear to involve activation of thrombin receptor, HIF-lc_ upregulation and increased transferrin, transferrin receptor and ferritin levels. This suggests that thrombin release during an ICH might induce protective mechanisms against factors released upon clot lysis. This data has led us to the following specific aims: 1) To determine whether TPC reduces hemorrhagic brain injury caused by lysis of erythrocytes. 2) To determine whether protease-activated receptors (PARs) play a key role in TPC. 3) To determine whether TPC modulates iron transport and storage protein levels in the brain, which then affects iron homeostasis after ICH. The purpose of our project is to investigate the mechanisms involved in TPC. An examination of TPC will also help our understanding of ischemic preconditioning since preliminary data suggests that TPC is a component of that phenomenon. It should be noted that TPC seems to be receptor mediated, greatly facilitating analysis compared to ischemic preconditioning. The long term goal of these studies is to find mechanisms that can be used to limit brain injury after ICH. PERFORMANCE SITE ========================================Section End===========================================